Tissue adhesives have many potential medical applications, including wound closure, supplementing or replacing sutures or staples in internal surgical procedures, adhesion of synthetic onlays or inlays to the cornea, drug delivery devices, and as anti-adhesion barriers to prevent post-surgical adhesions. Conventional tissue adhesives are generally not suitable for a wide range of adhesive applications. For example, cyanoacrylate-based adhesives have been used for topical wound closure, but the release of toxic degradation products limits their use for internal applications. Fibrin-based adhesives are slow curing, have poor mechanical strength, and pose a risk of viral infection. Additionally, the fibrin-based adhesives do not bond covalently to the underlying tissue.
Several types of hydrogel tissue adhesives have been developed, which have improved adhesive and cohesive properties and are nontoxic. These hydrogels are generally formed by reacting a component having nucleophilic groups with a component having electrophilic groups, which are capable of reacting with the nucleophilic groups of the first component, to form a crosslinked network via covalent bonding. However, these hydrogels typically swell or dissolve away too quickly, or lack sufficient adhesion or mechanical strength, thereby decreasing their effectiveness as surgical adhesives.
Kodokian et al. (copending and commonly owned U.S. Patent Application Publication No. 2006/0078536) describe hydrogel tissue adhesives formed by reacting an oxidized polysaccharide with a water-dispersible, multi-arm polyether amine. These adhesives provide improved adhesion and cohesion properties, crosslink readily at body temperature, maintain dimensional stability initially, do not degrade rapidly, and are nontoxic to cells and non-inflammatory to tissue. However, a tissue adhesive having these properties and also comprising a cationic polysaccharide to promote wound healing and blood coagulation, and provide antimicrobial properties would be highly desirable. Additionally, oxidized polysaccharides are known to have limited long-term stability when stored in aqueous solutions, which may restrict their commercial use.
Bentley et al. (U.S. Pat. No. 6,602,952) describe hydrogels derived from chitosan and poly(ethylene glycol), which are said to be useful as a drug delivery device, surgical sealant, or as a delivery system for a medical imaging agent. However, hydrogels derived from chitosan typically have poor mechanical properties because the poor aqueous solubility of chitosan limits the solids content that can be attained. Therefore, the need exists for a tissue adhesive that has good adhesion and mechanical strength, comprises a cationic polysaccharide to promote wound healing and blood coagulation, provides antimicrobial properties, and is formed from components that are stable in aqueous solution.